20-hydroxyeicosatetraenoic acid production inhibitors

ABSTRACT

A hydroxyformamidine compound represented by the following formula or a pharmaceutically acceptable salt thereof.  
                 
 
     [wherein R 1  represents a substituted morpholino group, a substituted piperidino group, a piperazin-1-yl group, a substituted piperazin-1-yl group, a thiomorpholin-1-yl group, a perhydroazepin-1-yl group, a perhydroazocin-1-yl group, a tetrahydropyridin-1-yl group, a pyrrolin-1-yl group, etc. ; X represents a nitrogen atom or a group represented by CR 5 ; and R 2  to R 5  are the same or different and each represents a hydrogen atom, a C 1-4  alkyl group, a C 1-4  alkoxy group, a trifluoromethyl group or a halogen atom.] 
     There is provided a drug which inhibits an enzyme producing 20-HETE participating in a contracting or dilating action for microvessels and an inducing action for cell proliferation in main organs such as kidney and cerebrovascular vessels.

TECHNICAL FIELD

[0001] The present invention relates to hydroxyformamidinobenzene orhydroxyamidinopyridine derivatives which inhibit the production of20-hydroxyeicosatetraenoic acid (20-HETE) from arachidonic acid.

BACKGROUND ART

[0002] With regard to physiologically active substances produced fromarachidonic acid, there have been widely known prostaglandins producedby cyclooxygenase and leucotrienes produced by lipoxygenase while, inrecent years, it has been becoming clear that 20-HETE produced fromarachidonic acid by enzymes belonging to cytochrome p450 genus hasvarieties of actions in vivo (J. Vascular Research, volume 32, page 79(1995)). Until now, it has been clarified that 20-HETE contracts ordilates the microvessels and also induces cell proliferation in mainorgans such as kidney and cerebrovascular vessels, and it has beensuggested that 20-HETE deeply participates in pathology of various renaldiseases, cerebrovascular diseases, circulatory diseases, etc. whileplaying an important physiological action in vivo (J. Vascular Research,volume 32, page 79 (1995); Am. J. Physiol., volume 277, page R607(1999); Physiol. Rev., volume 82, page 131 (2002), etc.).

[0003] An object of the present invention is to provide a drug whichinhibits the production of 20-HETE which participates in the contractionor dilation of microvessels, the induction of cell proliferation, etc.in main organs such as kidney and cerebrovascular vessels.

DISCLOSURE OF THE INVENTION

[0004] As a result of extensive searches and investigations for thepurpose of solving the above-mentioned problem, the present inventorshave found that several aromatic compounds inhibit the production of20-HETE, whereupon the present invention has been achieved.

[0005] That is, the present invention relates to a hydroxyformamidinecompound represented by the following formula or a pharmaceuticallyacceptable salt thereof.

[0006] [wherein R¹ represents a substituted morpholino group, asubstituted piperidino group, a piperazin-1-yl group, a substitutedpiperazin-1-yl group, a thiomorpholin-1-yl group, a perhydroazepin-1-ylgroup, a perhydroazocin-1-yl group, a tetrahydropyridin-1-yl group, apyrrolin-1-yl group, a 1,4-dioxa-8-azaspiro[4,5]decan-8-yl group, adecahydroquinolin-1-yl group, a mono- or di-(C₁₋₄ alkoxy-C₁₋₆alkyl)amino group, or a mono or di-(C₁₋₆ hydroxyalkyl)amino group; Xrepresents a nitrogen atom or a group represented by CR⁵; and R² to R⁵are the same or different and each represents a hydrogen atom, a C₁₋₄alkyl group, a C₁₋₄ alkoxy group, a trifluoromethyl group or a halogenatom.]

[0007] The terms used in the present invention are defined as follows.The substituted morpholino group means a morpholino group which issubstituted with 1 to 3 C₁₋₄ alkyl group(s) and its examples are2-methylmorpholino group, 2-ethylmorpholino group, 3-methylmorpholinogroup, 2,6-dimethylmorpholino group and 2,3,5-trimethylmorpholino groupwhere 2,6-dimethylmorpholino group is more preferred.

[0008] The substituted piperidino group means a piperidino group whichis substituted with a C₁₋₄ alkyl group, a piperidino group which issubstituted with a C₁₋₄ alkoxy group, a piperidino group which issubstituted with a hydroxyl group, a piperidino group which issubstituted with a C₂₋₅ alkoxycarbonyl group, a piperidino group whichis substituted with a mono- or di-C₂₋₇ alkylaminocarbonyl group, apiperidino group which is substituted with a C₁₋₄ alkoxy-C₁₋₆ alkylgroup, a piperidino group which is substituted with a C₁₋₆ hydroxyalkylgroup and a piperidino group which is substituted with a mono- ordi-C₁₋₄ alkylamino-C₁₋₆ alkyl group and its examples are2-methylpiperidino group, 3-methylpiperidino group, 4-methylpiperidinogroup, 4-ethylpiperidino group, 4-methoxypiperidino group,4-hydroxypiperidino group, 4-methoxycarbonylpiperidino group,4-ethoxycarbonylpiperidino group, 4-dimethylaminocarbonylpiperidinogroup, 3-diethylaminocarbonylpiperidino group, 4(2-methoxyethyl)piperidino group, 4-(2-hydroxyethyl)piperidino group and4- (2 -dimethylaminoethyl) piperidino group where 4-hydroxypiperidinogroup, 4-(2-hydroxyethyl)piperidino group, 4-ethoxycarbonylpiperidinogroup and 3-diethylaminocarbonylpiperidino group are more preferred.

[0009] The substituted piperazin-1-yl group means a piperazin-1-ylgroup, a piperazin-1-yl group which is substituted with a C₁₋₄alkylgroup, a piperazin-1-yl group which is substituted with a cycloalkylgroup having 4 to 8 ring members, a piperazin-1-yl group which issubstituted with a C₁₋₄ alkoxy-C₁₋₄ alkyl group, a piperazin-1-yl groupwhich is substituted with a C₁₋₆ hydroxyalkyl group, a piperazin-1-ylgroup which is substituted with a mono- or di-C₁₋₄ alkylamino-C₁₋₆ alkylgroup, a piperazin-1-yl group which is substituted with apyrrolidin-1-yl-C₁₋₆ alkyl group, a piperazin-1-yl group which issubstituted with a morpholinocarbonyl-C₁₋₆ alkyl group, a piperazin-1-ylgroup which is substituted with a C₂₋₆ alkanoyl group, a piperazin-1-ylgroup which is substituted with a phenyl group and a piperazin-1-ylgroup which is substituted with a pyridyl group and its examples are2-methylpiperazin-1-yl group, 3-methylpiperazin-1-yl group,4-methylpiperazin-1-yl group, 4-ethylpiperazin-1-yl group,4-cyclohexylpiperazin-1-yl group, 4-(2-methoxyethyl)piperazin-1-ylgroup, 4-(2-hydroxyethyl)piperazin-1-yl group,4-(2-dimethylaminoethyl)piperazin-1-yl group,4-(2-pyrrolidin-1-yl-ethyl)piperazin-1-yl group,4-(1-morpholinocarbonylmethyl)piperazin-1-yl group and4-phenylpiperazin-1-yl group where 4-methylpiperazin-1-yl group,4-ethylpiperazin-1-yl group, 4-cyclohexylpiperazin-1-yl group,4-(2-hydroxyethyl)piperazin-1-yl group,4-(2-dimethylaminoethyl)piperazin-1-yl group,4-(2-pyrrolidin-1-yl-ethyl)piperazin-1-yl group,4-(morpholinocarbonylmethyl)piperazin-1-yl group, 4-acetylpiperazin-1-ylgroup, 4-phenylpiperazin-1-yl group and 4-(2-pyridyl)piperazin-1-ylgroup are more preferred.

[0010] In the present invention, “C_(x-y)” means that a group thereafterhas x to y carbon atoms.

[0011] The halogen atom is fluorine atom, chlorine atom, bromine atom oriodine atom.

[0012] The C₁₋₄ and C₁₋₆ alkyl groups mean a linear or branched alkylgroup having 1-4 and 1-6 carbon atom(s), respectively and examples ofthe C₁₋₄ alkyl group are methyl group, ethyl group, propyl group,isopropyl group, butyl group, isobutyl group and tert-butyl group wheremethyl group is more preferred. Example of the C₁₋₆ alkyl group aremethyl group, ethyl group, propyl group, isopropyl group, butyl group,isobutyl group, tert-butyl group, pentyl group, isopentyl group, hexylgroup and isohexyl group where methyl group and ethyl group are morepreferred.

[0013] The C₁₋₄ alkoxy group means a linear or branched alkoxy grouphaving 1 to 4 carbon(s) and its examples are methoxy group, ethoxygroup, propoxy group, isopropoxy group, butoxy group and tert-butoxygroup.

[0014] The C₂₋₅ alkoxycarbonyl group means a substituent in a compoundedform of a linear or branched alkoxy group having 1 to 4 carbon(s) withcarbonyl group and its examples are methoxycarbonyl group,ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl groupand butoxycarbonyl group.

[0015] The mono- or di-C₂₋₇ alkylaminocarbonyl group means a substituentin a compounded form of an amino group, which is substituted with one ortwo linear or branched alkyl group(s) having 1 to 6 carbon (s), withcarbonyl group and its examples are methylaminocarbonyl group,ethylaminocarbonyl group, dimethylaminocarbonyl group,diethylaminocarbonyl group and diisobutylaminocarbonyl group wherediethylaminocarbonyl group is more preferred.

[0016] The C₁₋₄ alkoxy-C₁₋₄ alkyl group means a substituent in acompounded form of a linear or branched alkoxy group having 1 to 4carbon(s) with a linear or branched alkyl group having 1 to 4 carbon(s)and its examples are methoxymethyl group, ethoxymethyl group,methoxyethyl group, ethoxyethyl group, propoxyethyl group,isopropoxyethyl group, butoxyethyl group and tert-butoxyethyl group.

[0017] The C₁₋₆ hydroxyalkyl group means a linear or branched alkylgroup having 1 to 6 carbon(s) substituted with hydroxyl group and itsexamples are hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethylgroup, 3-hydroxypropyl group and 5-hydroxypentyl group where the morepreferred one is 2-hydroxyethyl group.

[0018] The mono- or di-C₁₋₄ alkylamino-C₁₋₆ alkyl group means asubstituent in a compounded form of an amino group, which is substitutedwith one or two linear or branched alkyl group(s) having 1 to 4carbon(s), with a linear or branched alkyl group having 1 to 6 carbon(s) and its examples are methylaminomethyl group, 1-methylaminoethylgroup, 2-methylaminoethyl group, 3-methylaminopropyl group,4-dimethylaminobutyl group, dimethylaminomethyl group,1-dimethylaminoethyl group, 2-dimethylaminoethyl group and3-dimethylaminopropyl group where 2-dimethylaminoethyl group is morepreferred.

[0019] The cycloalkyl group having 4 to 8 ring members means cyclobutylgroup, cyclopentyl group, cyclohexyl group, cycloheptyl group andcyclooctyl group where cyclohexyl group is more preferred.

[0020] The pyrrolidin-1-yl-C₁₋₆ alkyl group means a linear or branchedalkyl group having 1 to 6 carbon(s) substituted with a pyrrolidin-1-ylgroup and its examples are pyrrolidin-1-yl-methyl group, 2-(pyrrolidin-1-yl) ethyl group, 3-(pyrrolidin-1-yl)propyl group and5-(pyrrolidin-1-yl)pentyl group where 2-(pyrrolidin-1-yl)ethyl group ismore preferred.

[0021] The morpholinocarbonyl-C₁₋₆ alkyl group is a linear or branchedalkyl group having 1 to 6 carbon(s) substituted with amorpholinocarbonyl group and its examples are morpholinocarbonylmethylgroup, 2-morpholinocarbonylethyl group, 3-morpholinocarbonylpropyl groupand 5-morpholinocarbonylpentyl group where morpholinocarbonylmethylgroup is more preferred.

[0022] Melting points, measured MASS values, Rf values of TLC anddeveloping solvents of those compounds are shown in Table 1. In the TLCmeasurement, SiO₂ (NH) manufactured by Fuji Silysia Chemical Ltd. wasused.

[0023] The pharmaceutically acceptable salt is a salt with alkalinemetal, alkaline earth metal, ammonium, alkylammonium, etc. and a saltwith mineral acid or organic acid. Its examples are sodium salt,potassium salt, calcium salt, ammonium salt, aluminum salt,triethylammonium salt, acetate, propionate, butyrate, formate,trifluoroacetate, maleate, tartrate, citrate, stearate, succinate,ethylsuccinate, lactobionate, gluconate, glucoheptonate, benzoate,methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate,benzenesulfonate, p-toluenesulfonate, laurylsulfate, malate, aspartate,glutamate, adipate, a salt with cysteine, a salt with N-acetylcysteine,hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide,nicotinate, oxalate, picrate, thiocyanate, undecanoate, a salt withacrylic acid polymer and a salt with carboxyvinyl polymer.

[0024] The compound of the present invention can, for example, besynthesized by the method shown below. That is, a compound representedby the following formula (a):

[0025] (wherein Y is a halogen atom, and R², R³, R⁴ and X have the samemeanings as mentioned above) is made to react with a compoundrepresented by the following formula (b):

R¹H   (b)

[0026] (wherein R¹ has the same meaning as mentioned above) in thepresence or absence of a suitable solvent to give a compound representedby the following formula (c). (wherein R¹, R², R³, R⁴ and X have thesame meanings as mentioned above.)

[0027] Then, a nitro group of the compound (c) is reduced using areducing agent (such as palladium-activated carbon hydrogen in anatmosphere, palladium-activated carbon/hydrazine hydrate,palladium-activated carbon/ammonium formate, stannous (II) chloridemonohydrate, iron/ammonium chloride and Raney nickel/hydrazine hydrate)in a suitable solvent (such as methanol, ethanol, propanol,tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform,acetonitrile and ethyl acetate) to manufacture an aniline derivative(d). (wherein R¹, R², R³, R⁴ and X have the same meanings as mentionedabove.)

[0028] After that, the compound (d) is made to react withdimethylformamide dimethylacetal in a suitable solvent (such asmethanol, ethanol, propanol, tetrahydrofuran, dioxane, toluene,methylene chloride, chloroform, acetonitrile and ethyl acetate) at froma room temperature to 150° C., preferably 70° C. to 100° C. for 2 to 72hours. An intermediate which is prepared hereinabove is treated withhydroxylamine hydrochloride in a suitable solvent (such as methanol,ethanol, propanol, tetrahydrofuran, dioxane, toluene, methylenechloride, chloroform, acetonitrile and ethyl acetate) to manufacture thecompound of the present invention represented by the formula (1).Alternatively, the compound of the formula (d) is made to react with anorthoformate such as trimethyl orthoformate or triethyl orthoformate inthe presence or absence of a catalytic amount of an organic acid such asacetic acid, a mineral acid such as hydrochloric acid or a salt of aminewith mineral acid such as pyridine hydrochloride to give anintermediate. The reaction temperature is from a room temperature to150° C., preferably 70° C. to 100° C. and the reaction time is 2 to 72hours. This is isolated or is not isolated and then treated withhydroxylamine in a suitable solvent (such as methanol, ethanol,propanol, tetrahydrofuran, dioxane, toluene, methylene chloride,chloroform, acetonitrile and ethyl acetate) to manufacture the compoundof the present invention represented by the formula (1).

[0029] The medicine of the present invention contains the compoundrepresented by the formula (1) as such or a pharmaceutically acceptablesalt thereof as an effective ingredient. The medicine as such is usefulparticularly as a therapeutic agent for renal diseases, cerebrovasculardiseases or circulatory diseases. The inhibitor for the production of20-HETE according to the present invention contains the compoundrepresented by the formula (1) or a pharmaceutically acceptable saltthereof as an effective ingredient and it effectively inhibits theproduction of 20-HETE.

[0030] The dosage of the medicine, the treating agent for renaldiseases, cerebrovascular diseases and circulatory diseases, and theinhibitor for the production of 20-HETE according to the presentinvention is preferably 1 to 2,000 mg per day as the compoundrepresented by the formula (1) or a pharmaceutically acceptable saltthereof in the case of treatment of adults and it can be administeredonce or by dividing into several time daily. The dosage can beappropriately increased or decreased depending upon the use and age,body weight, symptom, etc. of the patient.

[0031] The medicine, the treating agent for renal diseases,cerebrovascular diseases and circulatory diseases, and the inhibitor forthe production of 20-HETE according to the present invention can beadministered either orally or parenterally. The dosage forms thereof aretablets, capsules, granules, diluted powder, powder, troches, ointments,creams, emulsions, suspensions, suppositories, injections, etc. and allof them can be manufactured by the ordinary preparation method (forexample, according to the methods stipulated by the 12th Revision of theJapanese Pharmacopoeia). Those dosage forms can be appropriatelyselected depending upon symptom, age and object of therapy of thepatient. In the manufacture of the preparations of various dosage forms,it is possible to use ordinary used excipients (such as crystallinecellulose, starch, lactose and mannitol), binders (such as hydroxypropylcellulose and polyvinylpyrrolidone), lubricants (such as magnesiumstearate and talc), disintegrating agents (such as carboxymethylcellulose calcium), etc.

BEST MODE FOR CARRYING OUT THE INVENTION

[0032] The present invention will now be illustrated in more detail byway of the following Examples.

EXAMPLE 1 Synthesis ofN-hydroxyl-N′-(3-chloro-4-thiomorpholinophenyl)formamidine

[0033] A mixture of 3-chloro-4-fluoronitrobenzene (0.070 g, 0.4 mmol)and thiomorpholine (0.165 g, 1.6 mmol) was stirred at 70° C. for 16hours. The reaction mixture was cooled down to room temperature,concentrated under a reduced pressure and purified by a silica gelcolumn chromatography (developing solvents; chloroform:methanol=9:1) toobtain yellow powdery crystals. Iron powder (0.27 g, 4.83 mmol),isopropanol (0.5 ml) and 1 equivalent of aqueous solution of ammoniumchloride (0.12 ml, 0.12 mol) were added thereto, followed by stirring at70° C. for 16 hours. The reaction mixture was cooled down to roomtemperature, tetrahydrofuran (0.4 ml) was added thereto and insolublematters were filtered off using Celite, followed by washing with ethylacetate (0.4 ml) for four times. The filtrate was concentrated under areduced pressure and methanol (0.4 ml) and dimethylformamidedimethylacetal (0.095 g, 0.8 mmol) were added thereto, followed bystirring at 70° C. for 64 hours. The reaction mixture was cooled down toroom temperature and concentrated under a reduced pressure and methanol(0.4 ml) and hydroxylamine hydrochloride (0.033 g, 0.48 mmol) were addedthereto, followed by stirring at room temperature for 6 hours. Thereaction mixture was concentrated under a reduced pressure and asaturated aqueous solution of sodium hydrogen carbonate (0.4 ml) wasadded thereto, followed by extracting with ethyl acetate. The organiclayer was concentrated under a reduced pressure, purified by an NH typesilica gel column chromatography (developing solvents; n-hexane:ethylacetate=1:1) and recrystallized from ethyl acetate/n-hexane to obtainthe title compound (0.026 g) (the compound 3 in Table 1 which will beshown after) in colorless powder.

[0034] Melting point: 137.0 to 138.5° C.

EXAMPLE 2 Synthesis ofN-[2-(morpholino)pyridine-5-yl]-N′-hydroxyformamidine

[0035] A mixture of 2-chloro-5-nitropyridine (2 g, 12.6 mmol) andmorpholine (4.4 g, 50.5 mmol) was stirred at a room temperature for 1hour. Water was added to the reaction mixture and the crystals separatedout therefrom were filtered to obtain yellow powdery crystals. Methanol(30 ml) and palladium carbon (0.25 g) were added thereto, the mixturewas stirred in a hydrogen atmosphere at a room temperature for 4 hours,insoluble matters were filtered off using Celite and the filtrate wasconcentrated under a reduced pressure. To the resulting residue wereadded methanol (20 ml) and dimethylformamide dimethylacetal (1.81 g,15.2 mmol), followed by stirring under refluxing for 2 hours. Thereaction mixture was cooled down to room temperature and concentratedunder a reduced pressure, and methanol (20 ml) and hydroxylaminehydrochloride (1.05 g, 15.2 mol) were added thereto, followed bystirring at room temperature for 4 hours. The reaction mixture wasconcentrated under a reduced pressure and a saturated aqueous solutionof sodium hydrogen carbonate (10 ml) was added thereto, followed byextracting with ethyl acetate. The organic layer was dried over MgSO₄,concentrated under a reduced pressure, purified by an NH type silica gelcolumn chromatography (developing solvents; n-hexane:ethyl acetate=1:1)and recrystallized from ethyl acetate to obtain the title compound(0.985 g) (the compound 127 in Table 1 which will be shown after) incolorless powder.

[0036] Melting point: 172.0 to 174.0° C.

[0037] The compounds shown in the following table were synthesized bythe same reaction operation as in Example 1 or 2 using the correspondingstarting materials. The compounds obtained in Examples 1 and 2 are alsoshown therein as compounds 3 and 127. Comp. M + H M − H Rf DevelopingIC₅₀ No. Structural Formula m.p. (APCl) (APCl) Value* Solvent (nM) 1

138.0-141.0 236 0.23 AcOEt 2

141.0-142.0 (dec.) 254 0.25 AcOEt 3.2 3

137.0-138.5 272 270 0.26 AcOEt 3.6 4

149.0-151.0 314 0.27 AcOEt 2.3 5

304 0.31 AcOEt 6

252 0.29 AcOEt 7

248 0.23 AcOEt 8

266 0.26 AcOEt 9

163.0-164.0 (dec.) 282 0.26 AcOEt 46.9 10

316 0.31 AcOEt 11

118.0-121.0 236 0.26 AcOEt 12.5 12

280 0.27 AcOEt 16.0 13

270 0.31 AcOEt 14

218 0.24 AcOEt 15

129.0-130.0 234 0.26 AcOEt 3.9 16

135.0-137.5 250 0.26 AcOEt 2.2 17

294 0.27 AcOEt 18

230 0.14 AcOEt 19

136.5-138.0 284 0.33 AcOEt 18.0 20

146.0-149.0 230 0.29 AcOEt 663.0 21

232 0.26 AcOEt 22

112.0-115.0 250 0.30 AcOEt 2.1 23

113.0-114.0 266 0.29 AcOEt 2.2 24

103.5-105.0 310 0.30 AcOEt 4.2 25

248 246 0.31 AcOEt 26

127.0-128.5 302 300 0.29 AcOEt 25.2 27

170.0-173.0 248 246 0.36 AcOEt 10.2 28

137.0-139.0 266 264 0.38 AcOEt 5.7 29

282 280 0.38 AcOEt 30

326 324 0.34 AcOEt 31

316 314 0.39 AcOEt 32

262 360 0.38 AcOEt 33

157.0-158.5 278 276 0.27 AcOEt 3.6 34

165.0-167.0 296 294 0.32 AcOEt 7.0 35

174.0-176.0 312 310 0.32 AcOEt 5.0 36

161.0-165.0 355 0.32 AcOEt 3.3 37

292 290 0.30 AcOEt 38

346 344 0.34 AcOEt 39

147.0-150.0 292 290 0.32 AcOEt 4.3 40

274 272 0.32 AcOEt 41

292 290 0.36 AcOEt 42

308 306 0.34 AcOEt 43

352 350 0.34 AcOEt 44

288 286 0.36 AcOEt 45

342 340 0.39 AcOEt 46

154.0-156.0 288 286 0.34 AcOEt 33 47

234 0.11 AcOEt 48

159.0-161.0 254 252 0.16 AcOEt 3.2 49

93.0-97.0 270 268 0.14 AcOEt 3.4 50

314 312 0.16 AcOEt 51

250 248 0.14 AcOEt 52

304 302 0.18 AcOEt 53

248 0.13 AcOEt 54

186.0-189.0 262 0.05 AcOEt 34.7 55

172.0-176.0 280 0.05 AcOEt 34.2 56

179.0-181.0 343 341 0.16 AcOEt 57

278 276 0.05 AcOEt 58

152.0-154.0 278 276 0.07 AcOEt 31.2 59

341 317 0.14 AcOEt 60

359 335 0.18 AcOEt 61

375 351 0.16 AcOEt 62

397 395 0.16 AcOEt 63

333 331 0.16 AcOEt 64

150-156.0 387 385 0.18 AcOEt 19.4 65

333 331 0.20 AcOEt 66

235 0.09 AcOEt 67

253 251 0.12 AcOEt 68

188.0-189.0 269 267 0.11 AcOEt 106.6 69

249 247 0.19 AcOEt 70

301 0.14 AcOEt 71

249 247 0.14 AcOEt 72

220.0-222.0 247 0.11 AcOEt 39.2 73

197.0-200.0 267 265 0.14 AcOEt 37.2 74

207.0-209.0 283 281 0.13 AcOEt 73.2 75

204.5-206.5 327 325 0.12 AcOEt 153.6 76

161.0-165.0 263 0.16 AcOEt 186.5 77

158.0-159.0 317 315 0.16 AcOEt 509.0 78

263 0.16 AcOEt 79

170.0 (dec.) 265 0.43 CHCl₃; MeOH = 10:1 71.9 80

180.0-182.0 (dec.) 283 281 0.39 CHCl₃; MeOH = 10:1 45.4 81

200.0-202.0 (dec.) 299 0.38 CHCl₃; MeOH = 10:1 23.3 82

190.0-192.0 (dec.) 343 0.38 CHCl₃; MeOH = 10:1 44.0 83

279 0.41 CHCl₃; MeOH = 10:1 84

333 331 0.34 CHCl₃; MeOH = 10:1 85

279 277 0.46 CHCl₃; MeOH = 10:1 86

188.0-190.0 (dec.) 292 0.46 CHCl₃; MeOH = 10:1 962.5 87

310 0.43 CHCl₃; MeOH = 10:1 88

326 324 0.44 CHCl₃; MeOH = 10:1 89

373 0.44 CHCl₃; MeOH = 10:1 90

360 358 0.41 CHCl₃; MeOH = 10:1 91

306 0.52 CHCl₃; MeOH = 10:1 92

318 0.51 CHCl₃; MeOH = 10:1 93

205.0 (dec.) 336 364 0.46 CHCl₃; MeOH = 10:1 135.4 94

161.0-163.0 352 0.46 CHCl₃; MeOH = 10:1 222.4 95

163.0-165.0 396 0.46 CHCl₃; MeOH = 10:1 75.8 96

229.0-231.0 (dec.) 386 384 0.43 CHCl₃; MeOH = 10:1 1534 97

196.0-198.0 (dec.) 332 330 0.51 CHCl₃; MeOH = 10:1 758.1 98

167.0-169.0 (dec.) 348 0.46 CHCl₃; MeOH = 10:1 69.0 99

366 0.44 CHCl₃; MeOH = 10:1 100

110.0-114.0 382 0.46 CHCl₃; MeOH = 10:1 36.3 101

426 0.46 CHCl₃; MeOH = 10:1 20.8 102

362 0.49 CHCl₃; MeOH = 10:1 103

75.0-77.0 416 414 0.46 CHCl₃; MeOH = 10:1 21.4 104

362 360 0.57 CHCl₃; MeOH = 10:1 105

226.0-223.0 (dec.) 303 0.48 CHCl₃; MeOH = 10:1 14.8 106

207.0 (dec.) 321 0.44 CHCl₃; MeOH = 10:1 105.4 107

337 0.44 CHCl₃; MeOH = 10:1 41.9 108

222.0-223.0 (dec.) 381 0.44 CHCl₃; MeOH = 10:1 293.0 109

317 0.49 CHCl₃; MeOH = 10:1 110

93.0-96.0 371 369 0.44 CHCl₃; MeOH = 10:1 531.2 111

230.0-232.0 (dec.) 317 0.56 CHCl₃; MeOH = 10:1 70.8 112

297 0.48 CHCl₃; MeOH = 10:1 113

315 297 0.46 CHCl₃; MeOH = 10:1 114

331 329 0.46 CHCl₃; MeOH = 10:1 115

375 373 0.46 CHCl₃; MeOH = 10:1 116

365 363 0.46 CHCl₃; MeOH = 10:1 117

311 0.61 CHCl₃; MeOH = 10:1 118

284 0.27 AcOEt 119

95.0-96.5 300 0.26 AcOEt 120

334 0.29 AcOEt 121

266 0.33 CHCl₃; MeOH = 10:1 122

349 0.44 CHCl₃; MeOH = 10:1 123

224.0-226.0 (dec.) 304 0.43 CHCl₃; MeOH = 10:1 90.6 124

249 247 0.38 AcOEt 125

279 277 0.23 AcOEt 126

237 235 0.31 AcOEt 127

172.0-174.0 221 0.22 AcOEt 215.4 128

172.0-174.0 215.4 129

191.0-192.0 (dec.) 8.3 130

189.0-190.0 (dec.) 46.1 131

94.0-96.0 3.5 132

151.0-153.0 37.3 133

97.0-98.0 340.5 134

135.0-138.0 (dec.) 4.0

TEST EXAMPLE Inhibitory Action to 20-HETE-Producing Enzyme derived fromHuman Renal Microsome

[0038] With regard to the compounds listed in the above table, theirinhibitory actions to 20-HETE production were tested.

[0039] This test was carried out in accordance with a method mentionedin J. Pharmacol. Exp. Ther., volume 268, page 474 (1994).

[0040] A solution of the test compound adjusted to 1 μM using DMSO wasadded to a 50 mM of 3-morpholinopropanesulfonic acid buffer (MOPS) (pH7.4) containing 5 mM of magnesium chloride and 1 mM of sodiumethylenediaminetetraacetate (EDTA), then human renal microsome fraction(Human Cell Culture Center, Anatomic Gift Foundation),[5,6,8,9,11,12,15]tritium-arachidonic acid and NADPH were added theretoas an enzymatic source, a substrate and a coenzyme, respectively andreaction was carried out at 37° C. for 1.5 hours. Formic acid was addedto the reaction solution to stop the reaction and then acetonitrile wasadded thereto (final concentration: 50%). Amount of 20-HETE producedthereby was measured using a high performance liquid chromatographyequipped with a radioactive substance detector having an ODS column(Biosil C18; manufactured by Biorad).

[0041] Amount of 20-HETE produced when no compound was added was definedas 100% and the concentration of the compound when production of 20-HETEwas inhibited to an extent of 50% upon addition of a compound (IC₅₀value) was calculated. The results are also shown in the above table.

INDUSTRIAL APPLICABILITY

[0042] The compound represented by the formula (1) or a pharmaceuticallyacceptable salt thereof is useful as an inhibitor for the production of20-HETE. It is also useful as a medicine, particularly as an agent forthe treatment of renal diseases, cerebrovascular diseases andcirculatory diseases.

1. A hydroxyformamidine compound represented by the following formula ora pharmaceutically acceptable salt thereof:

wherein R′ represents a substituted morpholino group, a substitutedpiperidino group, a piperazin-1-yl group, a substituted piperazin-1-ylgroup, a thiomorpholin-1-yl group, a perhydroazepin-1-yl group, aperhydroazocin-1-yl group, a tetrahydropyridin-1-yl group, apyrrolin-1-yl group, a 1,4-dioxa-8-azaspiro[4,5]decan-8-yl group, adecahydroquinolin-1-yl group, a mono- or di-(C₁₋₄ alkoxy-C₁₋₆alkyl)amino group, or a mono or di-(C₁₋₆ hydroxyalkyl)amino group; X isa nitrogen atom or a group represented by CR⁵; and R² to R⁵ are the sameor different and each represents a hydrogen atom, a C₁₋₄ alkyl group, aC₁₋₄ alkoxy group, a trifluoromethyl group or a halogen atom:
 2. Aninhibitor for production of 20-hydroxyeicosatetraenoic acid whichcomprises the hydroxyformamidine compound described in claim 1 or apharmaceutically acceptable salt thereof as an effective ingredient. 3.The inhibitor for production of 20-hydroxyeicosatetraenoic acidaccording to claim 2 which is an agent for the treatment of renaldiseases, cerebrovascular diseases and circulatory diseases.